Pneumocystis pneumonia (PCP) is a major opportunistic disease in patients with AIDS. Even with the highly active anti-retroviral therapy, PCP remains a significant problem in AIDS. At present, the most effective treatment for PCP is the combination of trimethoprim and sulfamethoxazole (TMP-SMX). Unfortunately, many AIDS patients with PCP fail therapy with this regimen. We have found that all-trans retinoic acid (ATRA) in combination with primaquine (PMQ), which is an 8-aminoquinoline, was as effective as TMP-SMX for treatment of PCP in both mice and rats. Since ATRA has some adverse effects, we tested vitamin D and found that in combination with PMQ, it is effective in suppressing the proliferation of Pneumocystis. We hypothesize that the vitamin D-PMQ combination can be optimized to become an ideal alternative treatment for PCP. We also hypothesize that the efficacy of some less effective drugs for PCP, such as atovaquone and dapsone, can be improved if they are used in combination with vitamin D. In this proposed project, the optimal doses of vitamin D and PMQ for PCP therapy will be determined. The hypothesis that vitamin D in combination with PMQ, dapsone, or atovaquone can be used for prophylaxis of PCP will also be examined. To explore the underlying mechanism of these novel therapies, the possibility that vitamin D strengthens host defense by reducing lung inflammation, promoting the production of antimicrobial peptides by alveolar macrophages (AMs), and restoring the number and function of AMs will be examined. The proposed studies will prove that the combination of vitamin D and primaquine, dapsone, or atovaquone is effective for treatment of PCP and establish the foundation for human clinical trials of the new regimen. The new therapy will eliminate the potential risk of sulf drug hypersensitivity associated with TMP- SMX, allowing patients who cannot tolerate TMP-SMX to be effectively treated.